Role of Zinc Supplementation in the Improvement of Acute Respiratory Infections among Iranian Children: A Systematic Review

Background: Respiratory infectious disease is considered as one of the most serious problems among children in developing countries. The importance of zinc in the improvement of respiratory disease has been indicated. However, there are some unanswered questions and uncertainty. This systematic review aimed at assessing the therapeutic benefits of zinc supplementation on respiratory infections of Iranian children. Materials and Methods: Databases, such as PubMed, Scopus, Embase, Magiran, and IranDoc, were searched for randomized controlled trials published from January 1998 to December 2017 on Zinc supplementation for the treatment or improvement of acute respiratory disease among Iranian children, during March 2018. Studies were screened according to the PICO framework, and irrelevant studies were excluded. Results: A total of 5 studies conducted on 522 children were included in this review. Except for one study, others had indicated the beneficial effect of zinc supplement on improving signs and symptoms of respiratory infectious disease and earlier discharge from the hospital. Conclusion: Although studies on the efficacy of zinc on respiratory infectious disease of children in Iran have not widely considered and more studies should be conducted, all published articles (except for one of them) had indicated the effectiveness of zinc supplementation on respiratory infections among children. Other criteria, such as age, gender, birth weight, diet, and type of respiratory infections, should be considered during zinc therapy. Controlling these confounding variables and measuring the level of blood zinc are necessary to understand how much zinc should be prescribed for respiratory treatment of children.


INTRODUCTION
Acute respiratory infections, such as pneumonia, are the most common underlying causes of illness and mortality among children (1)(2)(3)(4). Their prevalence of mortality is about 2 million deaths per year among children in low-income countries (5,6). Malnutrition, low birth weight, high population density, and air pollution are some most important risk factors for pneumonia in developing countries (7,8). Climate changes, rising air pollution, and population density in major cities of Iran in recent years have led to the further spread of such infections among vulnerable populations, such as children.
Zinc is one of the most important micro-nutrients, and its deficiency is common in developing countries, such as Iran. Malnutrition, lower level of meat consumption, and a higher level of consumption of cereals, such as white rice containing less zinc are some causes of zinc deficiency among children living in developing countries (1,10). Zinc deficiency in different cities of Iran has been reported in different cities of Iran (11)(12)(13)(14). Low levels of zinc in the blood of children can increase the risk of respiratory infections (1,15). Due to the protective and antiinflammatory properties of zinc, it plays an important role in preventing respiratory infections among children and promotes their health (7,16,17).
Several studies on various populations and age groups have indicated the role of zinc supplementation in improving the immune system and preventing infectious diseases (5,18,19). However, due to the contradictory evidence (20)(21)(22), and the effect of some variables, such as socioeconomic status, geographical location, race, ethnicity, age, and gender on the level of zinc (23)(24)(25), these confounding variables should be considered and controlled for an accurate evaluation. Some studies have been conducted in Iran on the effect of zinc on the prevention or treatment of infections (26,27,28,29,30,31

MATERIALS AND METHODS
This review was performed based on the guideline for meta-analyses and systematic reviews (PRISMA). To carry out this research, researchers initially reviewed studies Inclusion criteria were using eligible subjects, studies matched with the aims of the current study in terms of method, intervention, subjects, and outcome.

Search strategy
Databases, such as PubMed, Scopus, and Embase were searched in March 2018 for RCTs published from January 1998 to December 2017 using the following keywords: "Zinc" AND "Iranian children," "Zinc" AND "Iran" AND "children," "Zinc insufficiency," "Zinc deficiency," "Zinc status," "Zinc" AND "Respiratory infection," "Zinc" AND "Pneumonia" with the words "children" and "Iran," also in combination with "Iranian children." Iranian databases, such as Magiran and IranDoc, were also searched using identical Persian keywords. For manual search, references of the retrieved articles were reviewed.

RESULTS
During the search process, 2150 studies were found.
After three stages of screening based on the studies' titles and abstracts, 7 studies were eligible for full-text appraisals. After reviewing their full-text, one of the trials (4 groups, including three intervention groups and one control group) that was performed on children who referred to the healthcare center and evaluated the effect of zinc on the prevention of respiratory infections was deleted. Accordingly, only six studies with similar characteristics (RCTs with a control group) were selected for data analysis.

Description of the studies
We could not access to the full-text of one study  Table 1. study (27), 43.9% of the participants were less than one

Age
year old. In Qasemzadeh et al. study (28), gender and age were considered and controlled during the study. There were three age groups of less than 6 months, 6 months to 1 year, and 1 to 5 years.

Gender
In all studies, the proportion of male to female in both control and intervention groups was almost equal. Except for Heydarian et al. (30) study, this proportion was 74 boys and 50 girls.

The number of subjects
Regarding sample size, there was a fairly large difference between the studies. The highest and lowest sample sizes were 128 and 50 children, respectively.

Demographic criteria or disease diagnosis
Regarding differential diagnosis of the disease, in four studies, subjects had been selected based on two specific diagnoses (pneumonia (27,28) and bronchitis (29,30)). In one study, children with different kinds of respiratory infections were entered. The highest percentage (29%) was attributed to bronchitis, and other diseases, such as viral pneumonia, bacterial pneumonia, and the common cold, respectively (31). The onset of symptoms before the study was almost less than one week.

Methodologies of studies
Except for one study (28), other studies reported inclusion and exclusion criteria. In the study done by Heydarian et al. (30), the random allocation method of the subjects into two groups and the type of blindness was unclear; however, they had described how they fed the   Table   2, and some important criteria regarding the quality assessment of the studies are provided in Table 3.

DISCUSSION
None of the studies had measured the level of zinc in the blood of children before or after the intervention.
According to the studies, the child's birth weight, geographical area, air pollution, and population density are effective on the level of zinc in plasma (7,8). Therefore, measuring blood zinc levels in children before and after the intervention is useful to determine the effectiveness of the treatment (26,32).  breastfed or were formula-fed had been mentioned (27,29,30). Due to the important role of vitamins A and D on inflammation, daily intake of these vitamins in children should be considered.

LIMITATIONS
In this review, studies conducted in Iran were reviewed, and the results cannot be generalized. One of the most important limitations of our review was the lack of access to unpublished reports. Due to the lack of standardization of some studies or reporting findings inaccurately (before and after the intervention), combining the results, comparing the effect size, and analysis, the findings of the studies were impossible.